Treated-with-an-OAD-oral-antidiabetic-drug-monotherapy-69-with-metformin-and-had-HbA1c--or--10-were-enrolled-w

After a 4-week metformin run-in period, 210 subjects (27-73 years, 60% female) were randomised to receive liraglutide (045-05 mg) once daily or continued on metformin 1000 mg b.d. RESULTS: Mean baseline values for the six treatment groups ranged from 6 to 7% for HbA(1c), and 86-94 mmol/l (145-170 mg/dl) for fasting plasma glucose. After 12-week treatment, a weight change of -05 to -1% was observed for the six treatment groups. Mean HbA(1c) changes from baseline for 045, 025, 05, 0, 05 mg liraglutide and metformin were +18%, +06%, +02%, +06%, +00% and +09%, respectively. No significant differences in HbA(1c) were observed between liraglutide and metformin groups at the three highest liraglutide dose levels (05, 0 and 05 mg).

The lowest two liraglutide doses (045 mg and 025 mg) were not sufficient to maintain the fasting plasma glucose values achieved by metformin. No major hypoglycaemic episodes were reported. Episodes of nausea and/or vomiting were reported by 11 patients (6%) receiving liraglutide and three (8%) receiving metformin.CONCLUSIONS: Once-daily liraglutide improved glycaemic control and weight, in a comparable degree to metformin. glipizide 5 mg appeared to be safe and generally well tolerated. Higher doses of liraglutide merit study in future clinical Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (R.

E.K., J.J.H.), the Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Institute of Bioengineering (K.S.

), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L-cells, we observed that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca(2+). In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca(2+) response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT inhibition had no significant effect in nonpolarized primary cultures.

Studies in the perfused rat gut confirmed that vascularly administered TDCA was more effective than luminal TDCA. Intestinal primary cultures and Ussing chamber-mounted tissues from GPBAR1-knockout mice did not secrete GLP-1 in response to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice.Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators.

Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell-specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5'-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. glp 1 agonist has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R-targeting therapeutics.